Fosterdiagnostik med mikroarray för utökad analys av kromosomer

Prenatal Diagnosis through Chromosomal
Microarray Analysis (CMA)
sbu assessments | assessment of methods in health care and social services
february 2016 | www.sbu.se/246e
Executive summary
Conclusions
Chromosome
`` When one or more fetal anomalies are detected
by ultrasound, more genetic changes affecting
anatomy, development or function can be identified using Chromosomal microarray analysis
(CMA) than through karyotyping, QF-PCR,
Analysnivå:
or FISH analysis11. This applies in particular Teknik:
to anomalies detected in the heart or if the Visar:
anomalies were detected in more than one
organ system.
`` CMA reveals more genetic changes with unclear significance to anatomy, development or
function compared to karyotyping, QF-PCR
or FISH analysis.
`` For genetic changes that can be resolved with
karyotyping, QF-PCR or FISH analysis, CMA
has the same diagnostic accuracy as the reference test.
`` CMA can provide extensive information on an
individual’s genetic makeup. It is therefore of
utmost importance that the information obtained is used in an ethically acceptable manner.
Due to the extensive and complex nature of the
genetic information this test can provide, great
care and attention is required when presenting
the results to the clients to ensure the results
are fully understood. This is particularly true
1
QF-PCR and FISH analysis are two rapid diagnostic methods.
Stretch of DNA
illustration: mattias karlén
Kromosomernas utseende
Mindre delar av samtliga kromosomer
DNA-sekvensen
when presenting
unclear or unexpected
finKaryotypering
Mikroarray
Sekvensering
dings,
or
when
the
findings
relate
to
genetic
Tillkomst eller förlust av en hel
Tillkomst eller förlust av hel kromosom
Ordningsföljden av nukleotidbaser i
kromosom samt större synliga
eller mindre delar av en kromosom
deviations that
impact the future DNA-strängen,
health ”den
of genetiska
the koden”
förändringar
child to varying degrees.
Exempel: Trisomi, monosomi, balanserade
kromosomavvikelser samt stora
deletioner och duplikationer
`` Few additional genetic changes affecting anatomy, development or function are identified
using CMA beyond those detected through
karyotyping when the reason for testing is:
–– advanced age of the pregnant woman
–– parental anxiety
–– high probability of chromosomal abnorm­
ality based on maternal serum screening.
Piece of chromosome
Trisomi, monosomi, mikrodeletioner
och mikroduplikationer
Förlust, tillkomst eller balanserad
förändring av mindre delar av
DNA-sekvensen
`` Additional well-conducted studies are needed
to investigate how expectant parents perceive
the value of the information that CMA can
provide.
Background
CMA can be used to analyse the entire genetic
makeup of an individual and thereby detect genetic
changes that may affect anatomy, development or
function. These genetic changes, often referred to
as copy number variants (CNV), can be very large,
such as when an extra copy of a whole chromosome is
acquired. CNV can also refer to the loss or gain of a
much smaller piece of a chromosome.
A method called karyotyping has traditionally been
used to identify genetic changes prenatally. Karyotyping entails examining an individual’s chromosomes from cultured cells using a light microscope.
Karyotyping provides high diagnostic reliability for
detecting large CNV, including extra chromosomes
and major structural changes. However, CMA can
detect genetic changes that are more than 100 times
smaller than those detectable with karyotyping.
CMA is primarily used for prenatal diagnostics in
response to fetal anomalies detected by ultrasound,
such as structural aberrations in one or more organ,
abnormal growth of the fetus or placenta, or unusual
amniotic fluid volume.
sbu – swedish agency for health technology assessment and assessment of social services
1
Method
This evaluation is performed following SBU’s method.
Ethical and social aspects
Prenatal diagnosis raises ethical questions about
human dignity, parental autonomy, and the health
of both the fetus and the parents. This SBU report
presents ethically relevant advantages and challenges
associated with CMA compared to karyotyping.
General ethical aspects of prenatal diagnosis can be
found in a 2011 report from the Swedish National
Council on Medical Ethics.
The main advantage of using CMA for prenatal
diagnosis is that CMA can identify smaller genetic
changes than karyotyping. An important ethical
problem is the increased difficulty of fully informing
those involved about all of the potential findings in a
manner that is both clear and understandable. Secondary findings, and variants of uncertain significance
in particular, can cause concern and may be difficult
for parents to use in their decision making process.
Because CMA can detect more genetic changes than
karyotyping, it may lead to more problems from an
autonomy standpoint, i.e. the individual’s right to
self-determination. The increased use of CMA may
contribute to the perception that it is the parents’
responsibility to ensure that their offspring do not
2
have any genetically caused health problems. This
perception could make it more difficult for parents to
feel they can decline the offer of prenatal diagnosis.
Increased access to CMA may also allow healthcare
professionals to expand their perception of what entails a serious a condition. This could contribute to
stigmatisation of individuals with the genetic changes
that the method is capable of identifying.
Project group
Experts
Ann-Charlotte Thuresson (Associate Professor,
Clinical Molecular Geneticist, Uppsala)
Niklas Juth (Associate Professor, Senior Lecturer,
Stockholm)
Maria Soller (Associate Professor, Senior Physician,
Region Skåne)
SBU
Christel Hellberg (Project Manager)
Anna Attergren Granath (Project Administrator)
Agneta Brolund (Information Specialist)
Irene Edebert (Assistant Project Manager)
Miriam Entesarian Matsson (Assistant Project Manager)
Rebecca Silverstein (Assistant Project Manager)
Scientific reviewers
Jon Jonasson (Associate Professor, Senior Physician,
Region Östergötland)
Erik Iwarsson (Associate Professor, Senior Physician,
Stockholm)
Göran Lingman (Professor, Lund)
SBU Assessments no 246 (2016)
www.sbu.se/en • registrator@sbu.se
Graphic Design: Anna Edling, SBU
prenatal diagnosis through chromosomal microarray analysis (cma)
Article 246e
Objective
This report evaluates the reliability of the results
obtained from CMA for use in prenatal diagnostics.
It also evaluates how often additional genetic changes
are detected through CMA as compared to karyotyping, QF-PCR or FISH analysis. The report also
highlights ethical aspects of using CMA for prenatal
diagnosis, and how expectant parents perceive the
value of the analysis. Health economic aspects are not
addressed in this report.